qbd: a contract organization perspective

7/30/2019 QbD: A contract organization perspective

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ublished Articleharmaceutical Technology Outsourcing Resources

ugust 2012

Quality by Design: A ContractOrganizations Perspective

y Anil, Kane, Ph.D.

iew the full article at:

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y-by-Design-A-Contract-Organizations-Perspec/ArticleStan-

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2/5s20 Pharmaceutical Technology OutsOurcing resOurces 2012 PharmTech.com

Quality by Design

Whether the product and process is developed at onecontractors site, transferred from one contract de-veloper to another, or transferred from a sponsordevelopment unit to a contract development and

manufacturing organization (CDMO), knowledge transfer, anin-depth process understanding, identification of critical pro-cess parameters, and determination of proven acceptable processranges (PAR) are crucial to successful development. By failingto identify and correct the root causes of problems early in thedesign phase of the process- and product-development cycle, or-ganizations risk quality, yield, and supply-chain issues. Qualityby design (QbD) should be viewed as an opportunity that bringsvalue and business benefits to both the sponsor and the CDMO.

QbD benefits offered by a CDMOA CDMO supports the development of hundreds of molecularentities in different stages of clinical programs with small or largemolecules in sterile and nonsterile processes. A wealth of knowl-edge and experience resides with a CDMO that could be leveragedby a sponsor for new projects. Drawing on knowledge gained fromexperience, a CDMO can move quickly in identifying critical steps,building a robust model to plan, and designing experiments to ad-dress problems. We often find that when sponsors have changedhands due to licensing of new chemical entities, some informa-tion and documentation does not get transferred. A CDMO can

help the sponsor organize information, determine gaps, and workto build the program to meet the quality and regulatory require-ments. QbD requires a solid base of knowledge of the drug sub-stance, its physicochemical properties, characterization, raw ma-terial and excipient interactions and variability, and how all theseimpact the dosage form design, target product profile, and shelf-lifestability. A CDMO can leverage its inventory of knowledge andexperience, work with a sponsor to lay out a plan, and apply theprinciples of ICH Q8, Q9, and Q10 to develop a QbD strategy thatadds value to the sponsors program (13).

Current state of QbD: a CDMO viewA CDMO develops products for virtual companies, biotech,specialty, mid-size, large pharma, and generic drug companies,

Quality by Design: A Contract

Organizations PerspectiveOvercoming Obstacles to Implementing QbDAnil Kane

Quality by design (QbD) is based on sound

science and quality risk management throughwhich quality is built into products. Although

the benefits of QbD are obvious, the industry

has been relatively slow in adopting the

concept because QbD often falls low on the

list of immediate priorities. With product

development and manufacturing increasingly

being outsourced to contract development and

manufacturing organizations (CDMOs), however,

a strategic partnership between the sponsor and

a CDMO can help realize the benefits of QbD. The

author discusses how a CDMO helps in gaining

process understanding and in developing robust,

high-quality products and processes.

Anil Kane,PhD and MBA, is executive director of global

science and technology for pharmaceutical development

services at Patheon, 2100 Syntex Court, Mississauga, ON

L5N 7K9, Canada, tel: 905.812.6874. email: anil.kane@

patheon.com

ION-BOgDAN

DUMITRESCU/gETTyIMAgES


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Quality by Design

s22 Pharmaceutical Technology OutsOurcing resOurces 2012 PharmTech.com

and sees different philosophies and strategies adopted by spon-sors in applying QbD to product development. As key playersin industry, CDMOs need to move the QbD initiative forwardby helping sponsors and clients see potential benefits, so theywill give QbD a higher priority and understand the risks of notusing the QbD toolbox.

The benefits of using QbD at various stages of developmenthave been well documented. In a live poll conducted during aQbD conference, the majority of representatives from the in-dustry felt that it is never too late to adopt QbD and generatedata to get an in-depth process understanding (seeFigure 1) (4).

In a 2008 survey, 58% of the respondents said that their

QbD initiatives were only in the ideas and vision stage (5). In2010, at another QbD conference represented by the small,medium, large pharmaceutical, and generic drug sectors,results of a live poll, shown in Figure 2, indicated that morehad moved on from this stage (6).

Organizations have been slow in thinking about the bestway to implement the principles of QbD in their develop-ment programs as a part of their corporate strategy. Whenasked about the biggest obstacles, poll respondents answers,shown in Figure 3, indicated that pursuing QbD did not fitinto the priorities of many organizations (6).

Based on various discussions, Patheon has compiled commentsfrom the sponsors perspective as to reasons for not adopting QbDin their programs:

Our process is well developed and scalable. There maynot be any need for additional process development toset appropriate design space.

We need to meet aggressive timelines to ensure contin-ued funding. For virtual to small organizations, proofof concept and moving quickly to the next phase of theclinical program are of top priority.

Our goal is to have a product that will be successful inclinical trials. We can always optimize the process afterthe clinical phase is done.

This product will be partnered or sold post Phase 2b;why invest in QbD now?

There are regulatory risks associated with conductingQbD experimentation and the risk of delays due to largeexperimentation and possible reformulation in the latestages of development. This could also lead to an additionalbioequivalence study, which is costly and time-consuming.

We are reluctant to share development or proprietaryinformation (e.g., filing or historical data).

On the other hand, comments from CDMOs, compiled byPatheon from various discussions, offer a different perspec-tive on why QbD is worthwhile:

Many transferred processes are not well defined. Selec-

tion of excipients and their levels are not scientificallyjustified. Processes are scaled up to provide larger quan-tities of clinical trial supplies without sufficient data.

Figure 1: When is it too late to adopt a quality-by-design

approach to your product at a CDMO? (Ref. 4).

Figure 2: At what stage are quality-by-design initiatives

in your organization? (Ref. 6).

Figure 3: What is the biggest obstacle to pursuing quality by

design in your organization? (Ref. 6).

Figure 4: What is the biggest concern you have in conducting a

quality-by-design approach using a CDMO? (Ref. 4).

After preformulation,1%

After clinical phase2b; 8%

After commerciallaunch, 8%

After validation, 15%

Never too late; 68%

Roadmapdevelopment, 10%

Initialimplementation,

18%

Enrolledparticipants; 14%

Rolled out acrossorganization; 5%

Not started, 10%

Ideas & vision, 43%

Roadmapdevelopment, 10%

People resources;12%

Most people dontknow what it is; 20%

Not compatible withcompany culture; 5%

Initialimplementation,

18%

Too many other

things to do, 40%

Sharing ofproprietary

information; 14%

All of the above,36%

Lack of contractorsexpertise, 29%

Cost; 9%

Delays in projecttimeline, 13%

ALLFIgU

RESARECOURTESy

OFTHEAUTHOR


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Quality by Design


The failure rate in clinical trials is high. Using soundjudgment and a calculated risk-based approach, how-ever, will help move the clinical program forward bybalancing the scientific approach with capital invest-ment.

Often there is no time to optimize products in laterphases, which has impact on the cost of goods and se-curity of supply.

Failed batches and additional regulatory scrutiny willcause more delay than doing a systematic study cor-rectly now.

A well-understood, stable product developed usingsound QbD principles adds value to robust develop-ment, and the product is more attractive to potentialpartners for out-licensing.

The live-poll results in Figure 4 show that, when con-sidering conducting QbD with a CDMO, respondents are

concerned about project delays, cost, information sharing,and the expertise of the contractor (4). As more and moreproduct development is outsourced to a CDMO, however,sponsors will have to partner with CDMOs in pursuing theQbD strategy.

In recent years, Patheon has seen an increase in thenumber of sponsors/clients asking for QbD. Sponsorswould like to know what strategy a CDMO would proposeto proceed with this exercise and the experience level ofthe CDMO in designing a QbD work plan. More organiza-tions are now conducting statistical design-of-experiment

(DOE) studies to understand the design space for criticalprocess steps in solid oral and sterile dosage manufactur-ing operations.

Building a business caseCDMOs will typically have workedwith a larger variety of complexprocesses and challenging mol-ecules than their counterparts inindividual sponsor organizations.

The knowledge base gathered dur-ing many years and the experiencegained in resolving complex prob-lems can immensely help the spon-sor through the steps in the QbDprocess (see Figure 5).

A CDMO can design a phase-appropriate QbD strategy to buildquality into the product being devel-oped. An experimental plan shouldconserve API and consider time andcost. A CDMO can help in perform-ing an in-depth scientific risk assess-ment that will help in justifying theinvestment in a QbD exercise.

Because the financial invest-ment in QbD to a small or mediumsized organization can be huge, it

is important for the CDMO and sponsor to jointly builda business. It is not always possible to put a financial valueon everything we do. There also are business risks to thisinvestment, such as the possibility of the project costingmore, taking longer, or even failing due to a variety of de-

velopmental reasons.

A QbD case study at PatheonA case study illustrates the QbD process wherein Sponsor Xdeveloped a drug product and process in partnership withPatheon, by using QbD principles to ensure desired safety,efficacy, and quality of the product. Figure 6 depicts theoverall QbD strategy that was used.

A combination of prior knowledge and experimentalassessment during development were used to identify per-formance requirements (i.e., Stage 1), develop process un-derstanding, and conduct the criticality analysis. In Stage

2, critica l quality attributes (CQAs) of the drug productwere defined. An initial risk assessment was performedin Stage 3 to determine which process steps and materialscould control product CQAs. Stage 4 included a detailedcriticality analysis which evaluated the functional relation-ship between critical and key process parameters and CQAsto establish the design space. The design space includedthe control ranges of the key processing parameters andin-process parameters (IPCs) used to meet the CQAs fora safe, efficacious, and chemically stable drug product. Thedesign space defined by normal operating ranges (NORs)

and proven acceptable ranges (PARs) in conjunction withmaterial and product CQAs formed the basis of manufac-ture of the drug product. Process failure mode and effect

Figure 5: Steps in the quality-by-design process.

Dene initial qualitytarget product prole

Prior knowledge

Risk assessment

Knowledge space andcontrol space

For example, designof experiments

For example, processanalytical technology

Assign criticality(critical quality attributes)

Identify critical processparameters

Establish design space

Develop controlstrategy

Life-cycle management


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Quality by Design


analysis (FMEA) was conducted(Stage 5) prior to validation (Stage6), followed by continuous verifica-tion and improvement during com-mercial operation (Stage 7).

A detailed criticality analysis

was conducted on each materialattribute. Each aspect of the mate-rial was designated as critical, key,or noncritical based on its potentialto impact a CQA as illustrated inFigure 7.

Using the above systematic ap-proach based on sound science andquality risk management, SponsorX filed a QbD-based new drug ap-plication that was subsequently ap-proved, and t he product has been

successfully launched in the mar-ketplace.

ConclusionAs pharmaceutical companies part-ner with CDMOs for development,clinical, and commercial programs, the CDMO will play acritical role in jointly developing a QbD strategy to developrobust processes and quality products. Due to the wealthof knowledge gained by working on multiple, challengingmolecules, processes, and products, CDMOs are well posi-

tioned to support the sponsor in building a business case,justifying the investment, and applying risk assessment todrive QbD implementation.

References1. ICH, Q8 Pharmaceutical Development(2009).2. ICH, Q9 Quality Risk Management(2005).3. ICH, Q10 Pharmaceutical Quality System (2008).4. S. Closs, presentation at FDA/Xavier University Global Outsourc-

ing Conference (Cincinnati, OH, 2011).

5. J. Neway, BioPharm Intl.21 (12), 4247 (2008).6. A. Kane, presentation at FDA/Xavier University Global Outsourc-ing Conference (Cincinnati, OH, 2010). PT

Figure 7: Criticality analysis process flow. CQA is critical quality at tribute.

Figure 6: Quality-by-design process flow for a drug product (DP).

Amplitude of the effect,normal operating range vs.design space, closeness of

design space to edge of failure

Signicantpotential to

impact aCQA

Noncritical

KeyCritical

Highrisk

Risk assessment

YES

YES

NO

NO

Identify performancerequirements

Stage 1 Stage 2 Stage 3 Stage 4

Stage 5

Stage 6Stage 7

Identify critical qualityattributes (CQAs)

DP CQAs

Intermediate CQAs

Drug substance CQAs

Identify potentiallycritical process steps

and input materials

Continuous processverication andimprovement

Dene critical andkey process parameters,

operations in-processparameters, and

material attributes

Perform process failuremode and effect analysis

Conduct processvalidation

qbd: a contract organization perspective

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